Itch, or pruritus, is a common and distressing symptom in a variety of diseases. Pruritus typically occurs in peripheral diseases such as allergic conjunctivitis, allergic rhinitis, hemorrhoids, and dermatoses of fungal, allergic and non-allergic origin. Itching can also be a major symptom of certain systemic diseases such as, Hodgkin's disease, chronic renal failure, polycythema vera, hyperthyroidism and cholestasis (see, for example, Herndon, J. H. Jr., Int. J. Derm. 14, 465-484 (1975); Winkelmann, R. K., Med. Clins. N. Am. 66, 1119-1133 (1982)]. The clinical importance of pruritus is undeniable but research efforts in this area have been modest, to great extent due to the absence of established, specific experimental models, especially in preclinical research.
The intracutaneous injection of histamine or proteases elicits itch, and may be used as an experimental model for itch studies (Cormia, F. E., J. Invest. Derm. 19, 21 (1952); Shelley, W. B. and Arthur, R. P., Arch. Derm. (Chicago) 26, 296, 323 (1957)]. It was, therefore, postulated that these agents are involved as mediators in various itching conditions. Since histamine was believed to be the primary mediator of the itch sensation, conventional itch therapy involves H.sub.1 -antihistamines as a first-line medication. However, antihistamines have no general anti-pruritic effect, in many instances they are either ineffective or only partially effective. The physician is often obliged to resort to glucocorticoids to relieve pruritus but the potential undesirable side effects from glucocorticoid therapy are of great concern. Glucocorticoids cause skin atrophy and are absorbed systemically to cause Cushings disease-like effects. It has been concluded that although histamine is undoubtedly a potent pruritogen, at least one other itch-producing substance is involved in the clinically encountered spectrum of diseases where itch is a major symptom.
Although it is known that experimental pruritus may be evoked in human skin by the local administration of diverse pharmacologically active substances, the majority of which cause inflammation, demonstration that a chemical substance causes an itch sensation when locally administered does not necessarily mean that it is involved (as a mediator) in diseases in which itching is a symptom. Substances which have been reported to evoke or facilitate the itch sensation in human skin have not led to accepted anti-itch medications in those instances where compositions of matter are available to block the synthesis or activity of such substances. For example, according to Hagermark et al., J. Invest. Dermatol. 69, 527-539 (1977), prostaglandins E.sub.2 and H.sub.2 produce itch in human skin and potentiate the itch evoked by histamine. However, according to an earlier article by Hagermark [Acta Dermatovener 53, 363-368 (1973)) a known inhibitor of PGE.sub.2 synthesis, aspirin, did not act as an anti-pruritic agent, rather it actually prolonged experimental itch produced by trypsin or histamine. These experimental findings are amply supported by clinical experience where drugs like aspirin and indomethacin are not generally regarded as useful in treating itch.
The pruritogenic activity of other substances has been attributed to an indirect mechanism involving histamine release, these postulates being based on the activity systemically administered or locally injected H.sub.1 -antihistamines. Thus, synthetic platelet activating factor (PAF) has been reported to cause pruritus in human skin [Fjellner and Hagermark, Acta Derm. Venereol. 65, 409-412 1985)] "via indirect and mainly histamine-dependent mechanism". Based upon their experimental findings, the authors concluded that PAF probably produced itch in human skin by release of mast cell bound histamine.
Given the complicating factors which may confound interpretation of itching studies, proof of involvement of a substance in mediating itch is provided only by studies which demonstrate that a composition of matter which interferes with the synthesis of pharmacological action of the substance in question attenuates pruritus in either an experimental model of itching disease or in a study involving clinically encountered itch. Further, the beneficial effect of such a composition of matter in relieving itch should be demonstrated as independent of the actions of histamine.